An oral film is a solid oral dosage form containing at least one water soluble polymer in combination with other acceptable ingredients and can provide therapeutic, nutritional and/or cosmetic effects. The polymeric matrix carrying the pharmaceutical, nutritional and/or cosmetic ingredient(s) is molded in a thin layer of variable area and shape. In contrast to conventional oral dosage forms, the administration of an oral film does not require water. A preferred site of administration is the buccal cavity. The solid oral dosage film can be placed on the tongue, on the cheek pouch, under the tongue or in the inner labial mucosa. The film is designed to deliver a drug in a manner that facilitates absorption of the drug. Oral film technology may be the preferred solid dosage option when aiming for a rapid onset of action and avoidance of the ‘first-pass effect’ (hepatic metabolism). It can also be used when compliance of the patient is an issue and/or concern. Pediatric and geriatric patients, or those with swallowing issues, will benefit the most through the use of orally disintegrating film technology, and oral film dosage forms will be of particular convenience when a discrete administration is preferred.
The pharmaceutically employed oral film is formulated to exhibit instant hydration followed by a rapid dissolution/disintegration upon administration into the oral cavity. Upon administration and dissolution, the patient will not feel any discomfort during and/or immediately after its dissolution. The disintegration time can be varied through the suitable adjustment of the composition and physical properties of the matrix. Film forming polymers of common pharmaceutical use are water-soluble or water dispersible polymers that conform to the required properties, including, but not limited to, film instant hydration potential, mucoadhesion and solubility over time. Examples of film forming polymers include cellulose derivatives, polyvinyl alcohol, polyvinyl pyrrolidone, starches, polyacrylates, gums (xanthane gum, arabic gum, guar gum, etc.) and/or mixtures thereof. Film forming polymers may be used in combinations chosen based on the desired characteristics of the delivery form (e.g., rapid disintegration, higher mucoadhesion, longer residence time, etc.).
There are many major difficulties and challenges associated with the manufacture of oral film dosage forms ranging from brittleness, tackiness, the hygroscopic nature and potential lack of homogeneity within the dosage form. Ideal physical characteristics of the oral film include dosage uniformity throughout, adequate flexibility and tensile strength to facilitate processing, handling, and packaging of the film in a consumer-friendly form. Attaining ideal conditions for one characteristic usually comes at the expense of other, often equally important, properties, resulting in a necessary compromise in various properties to achieve a working film dosage form. Therefore, the main challenges and obstacles encountered when using oral film technology as a pharmaceutical delivery vehicle are due to the very properties upon which oral film technology is based. For example, challenges are encountered when attempting to provide an oral dosage as a film exhibiting a high content of liquid ingredients (0-35% wt/wt), and high drug loading in a matrix which is formulated as a very thin (under 80 micron) and continuous, yet flexible film layer.
An important requirement of modern drug delivery technology is the formulation of a delivery system that is capable of achieving a desirable release profile for the ever-increasing number of active pharmaceutical ingredients with limited to poor water solubility. Tadalafil for instance is practically insoluble in water. There are many conventional approaches for increasing the degree of solubilization of poorly soluble drugs including formation of ionizable molecules, pH adjustment and the development of co-solvent systems. However, these approaches can often be inadequate or inappropriate due to potential stability concerns. Particle size reduction has been a non-specific formulation approach that can be applied to almost any drug to enhance solubility. Due to greatly enhanced surface area obtained in this way, the dissolution rate and the bioavailability of poorly water-soluble drugs are expected to increase, After the solid dispersion is exposed to aqueous media and the carrier is dissolved, the drug is released as very fine, colloidal particles which can dissolve and be absorbed more rapidly than larger particles.
The increase in surface area results in a significant increase in surface energy leading to greater solubilization. However, the increase in surface energy is thermodynamically unfavorable and reagglomeration or crystallization/recrystallization of the particles is thermodynamically preferred resulting in a loss in the solubility of the material due to particle growth, and leading to decreased bioavailability. A preferred mechanism of stabilization of the reduced particles, for solid dosage forms, is physical stabilization of the particles through the dispersion of the particles on suitable polymers such as polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropylmethyl cellulose. This approach is often inadequate and leads to agglomeration and/or crystallization/recrystallization over time.
The key determinate properties in making an oral dosage film are the very particular features that facilitate the aggregation and/or crystallization to occur in an oral film relative to a classical solid dispersion (e.g. granulation, pellets, etc.). As discussed above, various technical approaches have been used to create solid solutions of a drug and to limit its reagglomeration or crystallization while increasing its bioavailability. Typically, the final product can have the shape of granules, pellets, or free flowing powder, and can subsequently be tableted or encapsulated. In the final product, the amount of water or any liquid ingredient in a solid oral dosage form is typically less than 5%. The active ingredient is finely dispersed (sometimes down to a molecular level size) and is in very close contact with large polymers that physically limit reagglomeration of the active ingredient. However, these techniques are not suitable for the production of oral films characterized by a physical continuity of the matrix and a high level of liquid ingredients necessary to impart flexibility and tensile strength to the film. The resulting chemical environment allows the drug molecules a certain freedom to move and aggregate at a greater rate relative to other types of solid oral dosage forms. Reducing the amount of ingredients that impart flexibility to the oral film is undesirable, as it would result in a rigid matrix with reduced tensile strength and that is difficult to manufacture on a large scale. The recrystallization, agglomeration and/or aggregation phenomena must be avoided to maintain high drug bioavailability and to prevent an undesirable change in the physical characteristics of the film (strength, appearance, homogeneity, stability, etc).
A homogenous and stable distribution of the drug in the film matrix is of primary concern when developing an oral film for buccal delivery of a pharmaceutically active ingredient. Any increase in particle size due to aggregation and/or crystallization of the particles must be avoided to enhance transmucosal absorption and to limit the gastrointestinal absorption upon disintegration of the dosage form. It is well known that within the buccal cavity the amount of biological fluids (saliva) available for the solubilization of a drug is very limited as compared with the gastrointestinal fluids. Therefore, any process promoting faster dissolution of the active ingredient is generally desirable, but increases the need for maintaining stability of the pharmaceutically active ingredient. In particular, stabilization of the reduced particle size is needed to facilitate effective transmucosal absorption. If the active ingredient were to agglomerate or to crystallize within the dosage form, its solubility will, correspondingly, decrease and will result in the active ingredient being swallowed with the saliva.
Another characteristic in determining the resistance of the drug to reagglomeration within films is the extremely thin physical continuity of the matrix which provides minimal physical resistance to particle migration, and makes it difficult to prevent reagglomeration of the pharmaceutically active ingredient. Further concern arising from conventional techniques is the increase in the susceptibility of the active to degradation due to the increase in available surface area.
The prior art does not fully address the difficulty associated with preparing a pharmaceutical oral film capable of delivering a film dosage form with stabilized increased solubility and enhanced bioavailability while maintaining essential film characteristics of the invention).
As mentioned above, tadalafil is practically insoluble in water, hence the difficulty in preparing oral film dosage form containing tadalafil API. Contrary to the manufacturing of tadalafil solid tablet dosage forms which do not require dissolution of tadalafil, oral film dosage forms require solubilizing of the API whether during the manufacturing of the film, once administered or both. Since tadalafil is particularly insoluble in water and only soluble in organic solvents that are not suitable for oral film dosage form (ex. DMSO, DMF), tadalafil oral film dosage form are not addressed by the prior art.